Mihai Bojinca

Management of rheumatoid arthritis: Impact and risks of various therapeutic approaches

Rheumatic diseases are highly prevalent chronic disorders and the leading cause of physical disability worldwide, with a marked socio-economic impact. Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown etiology with an autoimmune pathogenesis, characterised by arthropathy with chronic, deforming, destructive evolution and multiple systemic manifestations. The management of RA has undergone significant changes as far as objectives and approaches are concerned, ending in the current strategy known as ‘treat to target’. The therapeutic array of RA includes several categories of medicinal products, of varying potential. There are several criteria for the classification of medicinal products used against this disease, one of the most important and modern of which divides such substances according to their effects on the progress of the disease: symptom-modifying antirheumatic drugs (including non-steroidal anti-inflammatory drugs and corticoids), disease-modifying antirheumatic drugs (including various substances, such as gold salts, antimalarials, sulfasalazine, D-penicillamine; non-specific immunosuppressive medication, such as methotrexate, cyclophosphamide, azathioprine and leflunomide) and biological therapy is a recent addition, providing new insight into the treatment of this disease. The selection of the optimal therapy for RA should be based on guidelines and recommendations, but also on clinical particular aspects and patient preferences.

Association study in Romanians confirms IL23A gene haplotype block rs2066808/rs11171806 as conferring risk to psoriatic arthritis

BACKGROUND The cytokines IL12 and IL23 have been recently implicated in the pathogenesis of psoriatic arthritis (PsA). In this study we investigated the genetic variations in the genes coding for IL12, IL23 and IL23 receptor as a plausible source of susceptibility and modification of clinical symptoms of PsA in Romanian population. METHODS Twenty five SNPs mapping to IL12A, IL12B, IL23A, IL23R and IL12RB1 genes were genotyped in 94 PsA patients and 161 healthy controls of Romanian ethnicity using the Sequenom genotyping platform. RESULTS The exonic SNP rs11171806 from IL23A gene was significantly underrepresented in patients versus controls (p=0.03, OR 0.391) and the carriers of rs11171806/rs2066808 AC haplotype had decreased risk for PsA (p=0.03). The two SNPs of the highly conserved gene IL23A are in complete LD in our population. Genetic variants of IL12B gene were associated with polyarticular subtype of PsA. No associations were found between SNPs from IL12A, IL23R and IL12RB1 genes and susceptibility to PsA and its phenotypes. CONCLUSION We confirm the previously described association of rs2066808 variant with psoriasis and PsA and we show evidence of an extended genomic region inside IL23A gene as carrier of true disease susceptibility factors. These data suggest a role for IL23 in the PsA pathogenesis in Romanians.

Tenosynovitis US scoring systems follow synovitis and clinical scoring systems in RA and are responsive to change after biologic therapy.

AIMS To investigate by ultrasonography (US) in a cohort of active RA patients starting biologic therapy the responsiveness of tenosynovitis of wrist and hands compared to the responsiveness of synovitis in a 6 month period follow-up, to compare the responsiveness of finger flexor tenosynovitis with the responsiveness of wrist extensor tenosynovitis and to describe the subclinical synovitis and tenosynovitis in RA patients in clinical remission. MATERIAL AND METHODS Fifty seven patients with active RA starting biologic therapy were included. Clinical, laboratory, and US evaluations were performed at baseline, 1, and 6 months. US evaluation included wrist and MCPs 2-5 joints, bilaterally for synovitis and extensor tendons compartments 2, 4, and 6 and finger flexors 2-5 for tenosynovitis. Eighteen US scores based on semiquantitative or binary grades were calculated at each visit. Responsiveness of synovitis and tenosynovitis scores was calculated using the standardized response mean (SRM). RESULTS The responsiveness of US tenosynovitis was lower comparing with the responsiveness of US synovitis but both showed large effect of therapy. Furthermore, tenosynovitis responsiveness was similar to CRP responsiveness (SRM -0.90). Finger flexors tenosynovitis showed a higher responsiveness than extensor tenosynovitis on GS (-0.94 compared to -0.63) and a lower SRM on PD (-0.56 compared to -0.85). Tenosynovitis scores remission was overlapping clinical remission according to CDAI and SDAI in 100% of cases. Overall there was less subclinical tenosynovitis than subclinical synovitis at final visit according to clinical activity indices. CONCLUSION Tenosynovitis US scoring in RA may be as good as synovitis scoring for characterization of disease activity and responsiveness.

A Pilot Study of the Association of Tumor Necrosis Factor Alpha Polymorphisms with Psoriatic Arthritis in the Romanian Population

Tumor necrosis factor alpha (TNF-alpha) is an important pro-inflammatory cytokine implicated in the pathogenesis of psoriatic arthritis. We have performed a case-control association study of three TNF-alpha gene polymorphisms in a group of Romanian psoriatic arthritis patients versus ethnically matched controls. A second group of patients with undifferentiated spondyloarthritis was used in order to look for similarities in the genetic background of the two rheumatic disorders. The −857C/T polymorphism was associated with susceptibility to psoriatic arthritis in our population at the individual level (p = 0.03, OR 1.65, 95% CI 1.05–2.57) and in combined haplotypes with the −238G/A and −308G/A SNPs. Regarding the investigated polymorphisms and derived haplotypes, no potential association was found with the susceptibility to undifferentiated spondyloarthritis in Romanian patients.

Content validity of global measures for at-work productivity in patients with rheumatic diseases: an international qualitative study

OBJECTIVES To identify from a patients perspective, difficulties and differences in the comprehension of five global presenteeism measures in patients with inflammatory arthritis and OA across seven countries. METHODS Seventy patients with a diagnosis of inflammatory arthritis or OA in paid employment were recruited from seven countries across Europe and Canada. Patients were randomly allocated to be cognitively debriefed on 3/5 global measures [Work Productivity Scale - Rheumatoid Arthritis, Work Productivity and Activity Impairment Questionnaire (WPAI), Work Ability Index, Quality and Quantity questionnaire, and WHO Health and Work Performance Questionnaire (HPQ)], with the WPAI debriefed in all patients as a standard measure of comparison between countries and patients. NVivo was used to code the data into four themes: construct and anchor, time recall, reference frame, and attribution. RESULTS Discrepancies were found in the interpretation of the word performance (HPQ) between countries, with Romania and Sweden relating performance to sports rather than work. Seventy percent of patients considered that a 7-day recall (WPAI) can accurately represent how their disease affects work productivity. The compared to normal reference (Quality and Quantity questionnaire) was reportedly too ambiguous, and the comparison with colleagues (HPQ), made many feel uncomfortable. Overall, 29% of patients said the WPAI was the most relevant to them, making it the most favoured measure. CONCLUSION Overall, patients across countries agree that the construct of work productivity in the last 7 days can accurately reflect the impact of disease while at work. Some current constructs to assess at-work productivity are not interchangeable between languages.

Test-retest Reliability and Correlations of 5 Global Measures Addressing At-work Productivity Loss in Patients with Rheumatic Diseases

Objective. Several global measures to assess at-work productivity loss or presenteeism in patients with rheumatic diseases have been proposed, but the comparative validity is hampered by the lack of data on test-retest reliability and comparative concurrent and construct validity. Our objective was to test-retest 5 global measures of presenteeism and to compare the association between these scales and health-related well-being. Methods. Sixty-five participants with inflammatory arthritis or osteoarthritis in paid employment were recruited from 7 countries (UK, Canada, Netherlands, France, Sweden, Romania, and Italy). At baseline and 2 weeks later, 5 global measures of presenteeism were evaluated: the Work Productivity Scale–Rheumatoid Arthritis (WPS-RA), Work Productivity and Activity Impairment Questionnaire (WPAI), Work Ability Index (WAI), Quality and Quantity questionnaire (QQ), and the WHO Health and Performance Questionnaire (HPQ). Agreement between the 2 timepoints was assessed using single-measure intraclass correlations (ICC) and correlated between each other and with visual analog scale general well-being scores at followup by Spearman correlation. Results. ICC between measures ranged from fair (HPQ 0.59) to excellent (WPS-RA 0.78). Spearman correlations between measures were moderate (Qquality vs WAI, r = 0.51) to strong (WPS-RA vs WPAI, r = 0.88). Correlations between measures and general well-being were low to moderate, ranging from −0.44 ≤ r ≤ 0.66. Conclusion. Test-retest results of 4 out of 5 global measures were good, and the correlations between these were moderate. The latter probably reflect differences in the concepts, recall periods, and references used in the measures, which implies that some measures are probably not interchangeable.

Stevens‑Johnsons syndrome or drug‑induced lupus ‑ a clinical dilemma: A case report and review of the literature

Tumor necrosis factor inhibitors are the first biological agents used in the treatment of rheumatoid arthritis (RA) to have yielded satisfactory results in terms of clinical improvement and radiologic progression, but they are also associated with the possibility of occurrence of a number of autoimmune systemic events [drug-induced lupus (DIL), vasculitis, sarcoidosis] and localized adverse events [uveitis, psoriasis, interstitial lung disease, erythema multiforme including the major form Stevens-Johnson syndrome (SJS)]. During treatment with TNF inhibitors, many patients develop positivity for antinuclear, antihistone and anti-double stranded DNA antibodies, though only a minority of patients will develop clinical manifestations and approximately less than 1% will fulfill the classification criteria for systemic lupus erythematosus. Mucocutaneous manifestations are the most frequent manifestations of DIL following treatment with TNF inhibitors, and can be severe and occasionally difficult to differentiate from erythema multiforme/SJS. Stopping the causative drug (the TNF inhibitor) and general supportive measures are usually sufficient in mild forms, but in moderate to severe forms, systemic glucocorticoids and sometimes immunosuppressive drugs are required. The present report presents the case of a patient with rheumatoid arthritis who developed severe recurrent cutaneous reactions and positive autoantibodies during TNF inhibitor treatment, with difficulties in differential diagnosis and treatment. A review of the literature is also presented.

Difficulties in Diagnosis and Treatment of a Case of Cerebrotendinous Xanthomatosis (CBX)

The tendon pathology is very complex including traumatic, inflammatory and storage disorders. Cerebrotendinous Xanthomatosis (CBX) is a rare lipid storage disorder, characterized by the accumulation of fats in various areas of the body (mainly central nervous system and tendons). A mutation in the CYP27A1 gene leads to a deficient break down of cholesterol, who is responsible to the formation of a molecule called cholestanol which accumulates in different tissues. We present the case of a young woman presenting with bilateral Achilles tendon painful swelling and mild mental retardation.

Swollen Ankle Due to the Presence of Accessory Soleus Muscle - Case Report.

Swollen ankle might be a problem of differential diagnosis in young patients performing physical exercises. A mass on the posteromedial region of the ankle might be attributed to the presence of Accessory Soleus Muscle (ASM), the most common supernumerary muscle in the lower leg. We present the case of a young male with swelling and moderate pain on the posteromedial part of the right ankle after prolonged physical exercise. Musculoskeletal examination identified ASM. A conservative approach (symptomatic medication, physical therapy) was recommended with good results.

SAT0681 Risk of active tuberculosis in patients with inflammatory arthritis receiving tnf-inhibitors

Background Tuberculosis (TB) is a major concern in patients receiving TNF inhibitors (TNFi). Objectives To assess the incidence of active TB and the efficacy of TB prevention measures in a large, single-center cohort of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) receiving TNFi. Methods Data of all patients in whom treatment with TNFi was initiated in our rheumatology clinic from January 1st 2002 until December 31st 2015 have been retrospectively analysed. The cohort was divided into 2 groups per the mandatory latent TB infection (LTBI) screening method at baseline: tuberculin skin test (group TST), and QuantiFERON®-TB Gold test (group QFT). The incidence of active TB was analysed for each group and compared to TB incidence data in general population. Results 653 patients were included (344 RA, 52 PsA, 257 AS); 324 patients belonged to the TST and 329 to the QFT group. The number of active TB cases/ time of exposure to TNFi (person-years, PY) was 17/2002.6 and 7/1041.2 respectively, accounting for an incidence of 848.9 and 672.3 cases per 105 PY, about 8 times higher (8.3 and 8.8 for TST, respectively QFT group) than the average TB during the period of exposure to TNFi. LTBI reactivations per total TB cases were only 4/17 and 2/7, respectively, too few to identify statistically significant differences between the 2 LTBI screening protocols. Only 10 patients had pulmonary TB, whereas the rest were disseminated TB (8 cases), TB pleurisy and/or pericarditis (4 cases), one mediastinal lymph node TB and one isolated hepatic TB. Using Pearson chi-square test, we found no significant differences between LTBI group and active TB (Table 1).Table 1. LTBI screening results and TB occurrence in the 653 TNFi-treated patients (Pearson χ2 test) TST QFT All p value (n=324) (n=329) (n=653) Positive immuno-diagnostic test at baseline 52 (16.0%) 63 (19.1%) 115 (17.6%) <0.001* Active TB 17 (5.2%) 7 (2.1%) 24 (3.7%) 0.185* Reactivation TB 4 (1.2%) 2 (0.6%) 6 (0.9%) ** New infection TB 13 (4.0%) 5 (1.5%) 18 (2.8%) 0.052* Total TB incidence (per 105 PY) 848.9 672.3 788.5 – Maximal period of TNFi exposure in group 2002–2016 2011–2016 2002–2016 – Mean TB incidence in Romania in the respective time period (per 105 PY) 102.3 76.7 102.3 – TB incidence patients/general population 8.3 8.8 7.7 0.88† *Pearson χ2test comparing TST and QFT. **Reactivation TB cases were too few to perform statistical testing. †Pearson χ2test comparing total TB incidence in the TST and QFT groups to the average TB incidence in our region in the respective period of exposure. Conclusions In our cohort, new infection TB exceeds reactivation TB, suggesting the necessity of periodical LTBI re-screening. Disclosure of Interest A. M. Gheorghiu: None declared, A. Garaiman: None declared, A. Radu: None declared, A. Soare: None declared, V. Aramă: None declared, D. Bumbăcea: None declared, R. Dobrotă: None declared, R. Oneata: None declared, S. Pintilie: None declared, M. Milicescu Speakers bureau: Has received sponsoring from Abbvie, MSD and Pfizer., I. Ancuta Grant/research support from: Abbvie, Pfizer, Roche, UCB, BMS, Consultant for: Abbvie, Pfizer, Roche, UCB, BMS, Speakers bureau: Abbvie, Pfizer, Roche, UCB, BMS, A. Martin Grant/research support from: Abbvie, MSD, Pfizer, Roche, UCB, BMS, M. Sasu Grant/research support from: Abbvie, MSD, Pfizer, Roche, UCB, BMS, C. Ciofu Grant/research support from: Abbvie, MSD, L. Macovei Grant/research support from: MSD, Pfizer, Roche, V. Stoica: None declared, M. Bojinca Grant/research support from: Abbvie, MSD, Pfizer, Roche, UCB, BMS, Consultant for: Abbvie, MSD, Pfizer, Roche, UCB, BMS, Paid instructor for: Abbvie, MSD, Pfizer, Roche, UCB, BMS, C. Mihai Grant/research support from: Abbvie, MSD, Pfizer, Roche, UCB, BMS, Consultant for: Abbvie, MSD, Speakers bureau: Abbvie, MSD, Pfizer, Roche, UCB, BMS